US4387092A - Process for the preparation of factor VIII concentrate - Google Patents
Process for the preparation of factor VIII concentrate Download PDFInfo
- Publication number
- US4387092A US4387092A US06/237,135 US23713581A US4387092A US 4387092 A US4387092 A US 4387092A US 23713581 A US23713581 A US 23713581A US 4387092 A US4387092 A US 4387092A
- Authority
- US
- United States
- Prior art keywords
- polyol
- factor viii
- solution
- stage
- plasma
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 108010054218 Factor VIII Proteins 0.000 title claims abstract description 15
- 102000001690 Factor VIII Human genes 0.000 title claims abstract description 15
- 229960000301 factor viii Drugs 0.000 title claims abstract description 15
- 239000012141 concentrate Substances 0.000 title claims abstract description 4
- 238000000034 method Methods 0.000 title claims description 12
- 229920005862 polyol Polymers 0.000 claims abstract description 17
- 150000003077 polyols Chemical class 0.000 claims abstract description 17
- 239000000243 solution Substances 0.000 claims abstract description 12
- 239000006228 supernatant Substances 0.000 claims abstract description 8
- 102000008946 Fibrinogen Human genes 0.000 claims abstract description 7
- 108010049003 Fibrinogen Proteins 0.000 claims abstract description 7
- 229940012952 fibrinogen Drugs 0.000 claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 claims abstract description 3
- 239000008366 buffered solution Substances 0.000 claims abstract 4
- 239000002244 precipitate Substances 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 6
- 229920001223 polyethylene glycol Polymers 0.000 claims description 4
- 238000001556 precipitation Methods 0.000 claims description 4
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 2
- 229920000642 polymer Polymers 0.000 claims description 2
- 229940068918 polyethylene glycol 400 Drugs 0.000 claims 1
- 230000001376 precipitating effect Effects 0.000 claims 1
- 239000000047 product Substances 0.000 description 6
- 239000007853 buffer solution Substances 0.000 description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 102100026735 Coagulation factor VIII Human genes 0.000 description 2
- 108010067306 Fibronectins Proteins 0.000 description 2
- 102000016359 Fibronectins Human genes 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 101000911390 Homo sapiens Coagulation factor VIII Proteins 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- YBHYYFYQHRADCQ-UHFFFAOYSA-N 2-aminoacetic acid;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound NCC(O)=O.OC(=O)CC(O)(C(O)=O)CC(O)=O YBHYYFYQHRADCQ-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 101001027128 Homo sapiens Fibronectin Proteins 0.000 description 1
- 229920001030 Polyethylene Glycol 4000 Polymers 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- -1 for example Proteins 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 229940057838 polyethylene glycol 4000 Drugs 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/745—Blood coagulation or fibrinolysis factors
- C07K14/755—Factors VIII, e.g. factor VIII C (AHF), factor VIII Ag (VWF)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
- Y10S530/827—Proteins from mammals or birds
- Y10S530/829—Blood
- Y10S530/83—Plasma; serum
Definitions
- the resulting precipitate is made up of concentrated, purified factor VIII or antihemophilic factor, also called AHF.
- this process is preceded by a stage consisting in using a plasma solution or plasma cryoprecipitate as the starting product and adding about 4% polyol to said solution, eliminating the resulting fibrinogen precipitate and using the supernatant as the starting product in the process mentioned above.
- This preliminary stage was performed at a temperature of about 20° to 30° C.
- this preliminary purification stage can be replaced by another preliminary stage that consists in treating a factor VIII solution to be purified with a slight amount of polyol corresponding to a concentration less than 4%, while cooling at a temperature below 15° C.
- the major part of the fibrinogen and other impurities such as, for example, cold insoluble globulins (CIG) are eliminated by precipitation.
- CCG cold insoluble globulins
- this preliminary stage of the present invention can further be characterized by the following points, taken individually or in combination.
- the starting product such as those mentioned in the aforementioned patent, is used in the form of a buffer solution containing factor VIII to be purified; the starting product is, for example, a cryoprecipitate buffer solution or a plasma solution containing factor VIII.
- the impurities present in the starting product are fibrinogen and CIGs.
- Said starting solution is buffered at a pH between 6 and 7, and preferably 6.0 to 6.5.
- Polyol is added, preferably in a concentration of about 1 to 3%.
- the polyol can be, for example, polyethyleneglycol, preferably polyethyleneglycol 4000.
- Cooling is at a temperature between 0.5° and 15° C., generally between about +1° and +5° C. and in particular between about 2° and 4° C.
- Stirring is for a time that can vary from 5 minutes to 3 hours, preferably for about an hour, while cooling is maintained to keep the selected temperature, then centrifuging is performed still while cooling at a temperature below 15° C., preferably between +1° and +5° C., as indicated above.
- Cryoprecipitate (487 g) which is dissolved in 1920 ml of a buffer solution consisting of an aqueous solution of 0.02 M trisodium citrate and 0.1 M glycine with a pH 6.9 is used as the starting point.
- the pH is adjusted to 6.4 with citric acid and PEG 4000 is added in a 2% concentration (38.4 g). Cooling is to +2° C. and stirring is performed for an hour. Centrifuging is done with the temperature kept at +2° C. The precipitate is eliminated and the supernatant collected (1670 ml).
- the supernatant is treated according to the process of the aforementioned patent.
- the pH of the supernatant is adjusted to 6.9 by addition of NaOH, then 68 g of PEG (6%) are added still at +2° C.
- centrifuging is performed at +2° C. and the precipitate (14 g) of purified factor VIII is collected.
- the precipitate is redissolved in 400 ml of a citrate-glycine buffer solution, the pH is adjusted to 6.9 and the solution is subjected to a sterilizing filtration through micropore membrane filters having, for example, pores of a diameter of 1.2-0.65-0.45 and 0.3 microns.
- the resulting purified sterile factor VIII solution is lyophilized in the usual way.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biophysics (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Biochemistry (AREA)
- Toxicology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Hematology (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
An improved process for preparing factor VIII concentrate which comprises a first stage wherein fibrinogen is precipitated from a buffered plasma or plasma cryoprecipitate solution by the addition of a polyol and a second stage where factor VIII is precipitated from the resulting supernatant also by the addition of a polyol. The improvement in the first stage resides in adding the polyol in an amount of 1-3% and maintaining the temperature of the buffered solution between about 2°-4° C.
Description
In U.S. Pat. No. 4,069,216 there is described and claimed a process for preparing a factor VIII concentrate wherein it comprises the stage consisting in maintaining a buffer solution containing factor VIII and about 6% polyol at a temperature of about 0° to 5° C. until precipitation occurs.
The resulting precipitate is made up of concentrated, purified factor VIII or antihemophilic factor, also called AHF.
According to a particular embodiment, also described and claimed in the aforementioned patent, this process is preceded by a stage consisting in using a plasma solution or plasma cryoprecipitate as the starting product and adding about 4% polyol to said solution, eliminating the resulting fibrinogen precipitate and using the supernatant as the starting product in the process mentioned above.
This preliminary stage was performed at a temperature of about 20° to 30° C.
It has now been discovered that this preliminary purification stage can be replaced by another preliminary stage that consists in treating a factor VIII solution to be purified with a slight amount of polyol corresponding to a concentration less than 4%, while cooling at a temperature below 15° C. Thus, the major part of the fibrinogen and other impurities such as, for example, cold insoluble globulins (CIG) are eliminated by precipitation. By operation at low temperature, a purification is obtained at least as good as with the process at ambient temperature of the aforementioned patent, while a smaller amount of polyol is used.
According to preferred embodiments, this preliminary stage of the present invention can further be characterized by the following points, taken individually or in combination.
The starting product, such as those mentioned in the aforementioned patent, is used in the form of a buffer solution containing factor VIII to be purified; the starting product is, for example, a cryoprecipitate buffer solution or a plasma solution containing factor VIII. The impurities present in the starting product are fibrinogen and CIGs.
Said starting solution is buffered at a pH between 6 and 7, and preferably 6.0 to 6.5.
Polyol is added, preferably in a concentration of about 1 to 3%.
In a general way, the indications of concentrations, in the present invention, are by weight/volume.
The polyol can be, for example, polyethyleneglycol, preferably polyethyleneglycol 4000.
As other usable polyols, there will be cited in particular sequenced polymers of the polyoxyethylene-polyoxypropylene-polyoxyethylene type such as those sold under the name of Pluronic F-68.
Cooling is at a temperature between 0.5° and 15° C., generally between about +1° and +5° C. and in particular between about 2° and 4° C.
Stirring is for a time that can vary from 5 minutes to 3 hours, preferably for about an hour, while cooling is maintained to keep the selected temperature, then centrifuging is performed still while cooling at a temperature below 15° C., preferably between +1° and +5° C., as indicated above.
The resulting precipitate is eliminated and the supernatant is used as the starting product of the process described in said patent.
The following example illustrates the invention without, however, limiting it.
Cryoprecipitate (487 g) which is dissolved in 1920 ml of a buffer solution consisting of an aqueous solution of 0.02 M trisodium citrate and 0.1 M glycine with a pH 6.9 is used as the starting point.
After complete dissolving, the pH is adjusted to 6.4 with citric acid and PEG 4000 is added in a 2% concentration (38.4 g). Cooling is to +2° C. and stirring is performed for an hour. Centrifuging is done with the temperature kept at +2° C. The precipitate is eliminated and the supernatant collected (1670 ml).
Then the supernatant is treated according to the process of the aforementioned patent. For this, the pH of the supernatant is adjusted to 6.9 by addition of NaOH, then 68 g of PEG (6%) are added still at +2° C. After stirring to the end of precipitation, centrifuging is performed at +2° C. and the precipitate (14 g) of purified factor VIII is collected.
The precipitate is redissolved in 400 ml of a citrate-glycine buffer solution, the pH is adjusted to 6.9 and the solution is subjected to a sterilizing filtration through micropore membrane filters having, for example, pores of a diameter of 1.2-0.65-0.45 and 0.3 microns.
The resulting purified sterile factor VIII solution is lyophilized in the usual way.
Claims (7)
1. In a process for preparing Factor VIII concentrate where in a first stage fibrinogen is precipitated from a solution of plasma or plasma cryoprecipitate from a buffered solution having a pH ranging between 6 and 7 by the addition of a polyol and the precipitate comprising fibrinogen is removed to provide a supernatant comprising Factor VIII and in a second stage said Factor VIII is precipitated from said supernatant by increasing the polyol concentration to at least about 6% and holding the solution containing said increased amounts of polyol at from about 0° to about 5° until precipitation of said Factor VIII occurs, the improvement comprising the steps of in said first stage of precipitating fibrinogen from a solution of plasma or plasma cryoprecipitate from said buffered solution by the addition of a polyol in an amount of about 1 to 3% while cooling said solution to a temperature between about 2° and 4° C.
2. The process of claim 1 wherein said pH ranges from 6.0 to 6.5.
3. The process of claim 1 where in said first stage said buffered solution is stirred for a period of time ranging from 5 minutes to 3 hours while maintaining the temperature thereof at the selected temperature.
4. The process of claim 1 wherein the polyol is polyethylene glycol.
5. The process of claim 4 wherein said polyethyleneglycol is polyethyleneglycol 400.
6. The process of claim 1 wherein said polyol is a sequenced polymer of the polyoxyethylene-polyoxypropylene-polyoxyethylene type.
7. The process of claim 6 wherein said polyol is Pluronic-68.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7916966A FR2460305A2 (en) | 1979-06-29 | 1979-06-29 | PROCESS FOR PREPARING A FACTOR VIII CONCENTRATE |
| FR7916966 | 1979-06-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US4387092A true US4387092A (en) | 1983-06-07 |
Family
ID=9227339
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US06/237,135 Expired - Fee Related US4387092A (en) | 1979-06-29 | 1980-06-30 | Process for the preparation of factor VIII concentrate |
Country Status (3)
| Country | Link |
|---|---|
| US (1) | US4387092A (en) |
| FR (1) | FR2460305A2 (en) |
| WO (1) | WO1984000757A1 (en) |
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4543210A (en) * | 1984-10-04 | 1985-09-24 | Miles Laboratories, Inc. | Process for producing a high purity antihemophilic factor concentrate |
| US4650858A (en) * | 1983-03-21 | 1987-03-17 | Nordisk Gentofte A/S | Concentrate of the antihemophilic factor VIII and a process for producing it |
| US4739039A (en) * | 1985-11-08 | 1988-04-19 | Baxter Travenol Laboratories, Inc. | Method for preparing antihemophilic factor (AHF) by cold precipitation and for improving solubility of recovered AHF product |
| US4743680A (en) * | 1985-02-01 | 1988-05-10 | New York University | Method for purifying antihemophilic factor |
| US4847362A (en) * | 1985-02-01 | 1989-07-11 | New York University | Method for purifying antihemophilic factor |
| US4952675A (en) * | 1985-02-01 | 1990-08-28 | New York University | Method for purifying antihemophilic factor |
| US5576291A (en) * | 1993-09-13 | 1996-11-19 | Baxter International Inc. | Activated factor VIII as a therapeutic agent and method of treating factor VIII deficiency |
| US5618789A (en) * | 1984-04-20 | 1997-04-08 | Genentech, Inc. | Functional human factor VIII |
| US5824780A (en) * | 1993-07-23 | 1998-10-20 | Baxter International Inc. | Activated human factor VIII and method of preparation |
| US6586573B1 (en) | 1999-02-22 | 2003-07-01 | Baxter International Inc. | Albumin-free Factor VIII formulations |
| US20080306610A1 (en) * | 2007-06-07 | 2008-12-11 | Zimmer Orthobiologics, Inc. | Tissue processing for nonimmunogenic implants |
| US20100168018A1 (en) * | 2008-11-07 | 2010-07-01 | Baxter International Inc. | Factor viii formulations |
| US8753406B2 (en) | 2010-08-31 | 2014-06-17 | Zimmer Inc. | Osteochondral graft delivery device and uses thereof |
| WO2022099223A2 (en) | 2020-11-09 | 2022-05-12 | Takeda Pharmaceutical Company Limited | Purification of fviii from plasma using silicon oxide adsorption |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AT369263B (en) * | 1980-08-27 | 1982-12-27 | Immuno Ag | METHOD FOR PRODUCING A FACTOR VIII (AHF) HIGH CONCENTRATE |
| ATE90875T1 (en) * | 1989-05-24 | 1993-07-15 | Miles Inc | GEL FILTRATION OF HEAT-TREATED FACTOR VIII. |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3631018A (en) * | 1970-05-01 | 1971-12-28 | Baxter Laboratories Inc | Production of stable high-potency human ahf using polyethylene glycol and glycine to fractionate a cryoprecipitate of ahf concentrate |
| US3770631A (en) * | 1971-06-29 | 1973-11-06 | Baxter Laboratories Inc | Clarification of blood serum and plasma |
| US4069216A (en) * | 1975-06-16 | 1978-01-17 | Edward Shanbrom, Inc. | Simplified methods for preparation of very high purity Factor VIII concentrate |
| US4085095A (en) * | 1976-01-22 | 1978-04-18 | Rodger L. Bick | Clottable fibrinogen free Factor VIII product and process |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1350895A (en) * | 1962-01-03 | 1964-01-31 | South African Inventions | Precipitation of organic colloids |
| BE713764A (en) * | 1967-05-01 | 1968-09-16 | Baxter Travenol Lab | |
| US4057628A (en) * | 1976-04-19 | 1977-11-08 | William L. Wilson | Removal of hepatitis associated antigen from plasma |
| FR2363577A1 (en) * | 1976-09-03 | 1978-03-31 | Recherches Hematologiques | Concn. and purification of plasma antihaemophilic factor - by cryoprecipitation , extn. into water, cooling to ppte. fibrinogen and lyophilising |
-
1979
- 1979-06-29 FR FR7916966A patent/FR2460305A2/en active Granted
-
1980
- 1980-06-30 US US06/237,135 patent/US4387092A/en not_active Expired - Fee Related
- 1980-06-30 WO PCT/FR1980/000102 patent/WO1984000757A1/en unknown
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3631018A (en) * | 1970-05-01 | 1971-12-28 | Baxter Laboratories Inc | Production of stable high-potency human ahf using polyethylene glycol and glycine to fractionate a cryoprecipitate of ahf concentrate |
| US3770631A (en) * | 1971-06-29 | 1973-11-06 | Baxter Laboratories Inc | Clarification of blood serum and plasma |
| US4069216A (en) * | 1975-06-16 | 1978-01-17 | Edward Shanbrom, Inc. | Simplified methods for preparation of very high purity Factor VIII concentrate |
| US4085095A (en) * | 1976-01-22 | 1978-04-18 | Rodger L. Bick | Clottable fibrinogen free Factor VIII product and process |
Cited By (30)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4650858A (en) * | 1983-03-21 | 1987-03-17 | Nordisk Gentofte A/S | Concentrate of the antihemophilic factor VIII and a process for producing it |
| US5618788A (en) * | 1984-04-20 | 1997-04-08 | Genentech, Inc. | Preparation of functional human factor VIII and pharmaceutical treatment therewith |
| US5683905A (en) * | 1984-04-20 | 1997-11-04 | Genentech, Inc. | Vectors and cell lines capable of correctly splicing exon regions |
| US5668108A (en) * | 1984-04-20 | 1997-09-16 | Genentech, Inc. | Preparation of functional human factor VIII and pharmaceutical treatment therewith |
| US5654147A (en) * | 1984-04-20 | 1997-08-05 | Genentech, Inc. | Method of hybridization using oligonucleotide probes |
| US5633150A (en) * | 1984-04-20 | 1997-05-27 | Genentech, Inc. | Preparation of functional human factor VIII |
| US5618789A (en) * | 1984-04-20 | 1997-04-08 | Genentech, Inc. | Functional human factor VIII |
| US4543210A (en) * | 1984-10-04 | 1985-09-24 | Miles Laboratories, Inc. | Process for producing a high purity antihemophilic factor concentrate |
| US4743680A (en) * | 1985-02-01 | 1988-05-10 | New York University | Method for purifying antihemophilic factor |
| US4952675A (en) * | 1985-02-01 | 1990-08-28 | New York University | Method for purifying antihemophilic factor |
| US4847362A (en) * | 1985-02-01 | 1989-07-11 | New York University | Method for purifying antihemophilic factor |
| US4739039A (en) * | 1985-11-08 | 1988-04-19 | Baxter Travenol Laboratories, Inc. | Method for preparing antihemophilic factor (AHF) by cold precipitation and for improving solubility of recovered AHF product |
| US5824780A (en) * | 1993-07-23 | 1998-10-20 | Baxter International Inc. | Activated human factor VIII and method of preparation |
| US5576291A (en) * | 1993-09-13 | 1996-11-19 | Baxter International Inc. | Activated factor VIII as a therapeutic agent and method of treating factor VIII deficiency |
| US6586573B1 (en) | 1999-02-22 | 2003-07-01 | Baxter International Inc. | Albumin-free Factor VIII formulations |
| US8058226B2 (en) | 1999-02-22 | 2011-11-15 | Baxter International Inc. | Albumin-free factor VIII formulations |
| US7087723B2 (en) | 1999-02-22 | 2006-08-08 | Baxter International Inc. | Albumin-free factor VIII formulations |
| US20060205661A1 (en) * | 1999-02-22 | 2006-09-14 | Baxter International, Inc. | Novel albumin-free factor VIII formulations |
| US7247707B2 (en) | 1999-02-22 | 2007-07-24 | Baxter International Inc. | Albumin-free factor VIII formulations |
| US9669076B2 (en) | 1999-02-22 | 2017-06-06 | Baxalta Incorporated | Albumin-free factor VIII formulations |
| US9352027B2 (en) | 1999-02-22 | 2016-05-31 | Baxalta Incorporated | Albumin-free factor VIII formulations |
| US20040116345A1 (en) * | 1999-02-22 | 2004-06-17 | Marc Besman | Novel albumin-free factor VIII formulations |
| US8372800B2 (en) | 1999-02-22 | 2013-02-12 | Baxter International Inc. | Albumin-free factor VIII formulations |
| US8765665B2 (en) | 1999-02-22 | 2014-07-01 | Baxter International Inc. | Albumin-free factor VIII formulations |
| US20080306610A1 (en) * | 2007-06-07 | 2008-12-11 | Zimmer Orthobiologics, Inc. | Tissue processing for nonimmunogenic implants |
| US20100168018A1 (en) * | 2008-11-07 | 2010-07-01 | Baxter International Inc. | Factor viii formulations |
| US10512674B2 (en) | 2008-11-07 | 2019-12-24 | Baxalta Incorporated | Factor VIII formulations |
| US11020459B2 (en) | 2008-11-07 | 2021-06-01 | Baxalta Incorporated | Factor VIII formulations |
| US8753406B2 (en) | 2010-08-31 | 2014-06-17 | Zimmer Inc. | Osteochondral graft delivery device and uses thereof |
| WO2022099223A2 (en) | 2020-11-09 | 2022-05-12 | Takeda Pharmaceutical Company Limited | Purification of fviii from plasma using silicon oxide adsorption |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1984000757A1 (en) | 1984-03-01 |
| FR2460305B2 (en) | 1983-07-22 |
| FR2460305A2 (en) | 1981-01-23 |
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Legal Events
| Date | Code | Title | Description |
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